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An aging mouse model of human chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival. This model was developed by noncytotoxic depletion of bone marrow lineage-positive cells followed by BCR-ABL retroviral transduction and transplantation. CML developed in aging mice shared many similarities to that in young mice, but had increased incidence of anemia that is often seen in human CML. Importantly, we showed that aging of both donor hematopoietic stem cells and recipient bone marrow niche impacted BCR-ABL mediated leukemogenesis and leukemia spectrum. Optimal CML induction relied on age-matching for donors and recipients, and cross-transplantation between young and old mice produced a mixture of different leukemia. Therefore, our model provides initial evidence of the feasibility and merit of CML modeling in aging mice and offers a new tool for future studies of CML stem cell drug resistance and therapeutic intervention in which aging would be taken into consideration as an influencing factor.

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Fig. 1: The impact of aging on baseline hematological parameters in BALB/c mice.
Fig. 2: The 5-FU myeloablation protocol was not suitable for CML induction in aging BALB/c mice.
Fig. 3: Efficient CML induction in aging BALB/c mice by the immunomagnetic lineage depletion protocol.
Fig. 4: Histopathology of CML in aging mice.
Fig. 5: Aging of both HSCs and bone marrow niche affected the pathogenesis of CML.

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Acknowledgements

This work was supported by the grants UH2/3 CA213385 (co-sponsored by NIH National Cancer Institute and National Institute of Aging) and 3UH3CA213385-05S1 (sponsored by NIH Office of the Director), as well as institutional grants from the City of Hope Center for Cancer and Aging, and Norton Basic Research Fund to WYC. Research reported in this publication included work performed in the Animal Resources Center and Flow Cytometry Core supported by the National Cancer Institute under the award P30CA33572. The content is solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Hao, T., Zhang, C., Wang, Z. et al. An aging mouse model of human chronic myeloid leukemia. Oncogene 40, 3152–3163 (2021). https://doi.org/10.1038/s41388-021-01770-0

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